Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000070.3(CAPN3):c.2134C>T (p.Leu712Phe)

CA241878

195450 (ClinVar)

Gene: CAPN3 (HGNC:825)

Condition: autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152)

Inheritance Mode: Autosomal recessive inheritance

UUID: dee1b669-400a-4ed1-930d-64adb51d4ceb

Approved on: 2026-04-29

Published on: 2026-05-07

HGVS expressions

NM_000070.3(CAPN3):c.2134C>T (p.Leu712Phe)

NM_000070.3:c.2134C>T

NC_000015.10:g.42410446C>T

CM000677.2:g.42410446C>T

NC_000015.9:g.42702644C>T

CM000677.1:g.42702644C>T

NC_000015.8:g.40489936C>T

NG_008660.1:g.67344C>T

ENST00000337571.9:c.139C>T

ENST00000349748.8:c.1858C>T

ENST00000357568.8:c.2116C>T

ENST00000397163.8:c.2134C>T

ENST00000397204.9:c.139C>T

ENST00000466222.7:n.399C>T

ENST00000466369.5:n.2625C>T

ENST00000495723.1:n.3005C>T

ENST00000549793.5:n.2347C>T

ENST00000562199.2:c.138C>T

ENST00000569136.6:c.139C>T

ENST00000638141.2:n.1873C>T

ENST00000673646.1:c.698C>T

ENST00000673684.1:n.116C>T

ENST00000673687.1:n.643C>T

ENST00000673692.1:c.139C>T

ENST00000673705.1:c.511-142C>T

ENST00000673743.1:c.37C>T

ENST00000673750.1:c.139C>T

ENST00000673771.1:c.139C>T

ENST00000673774.1:n.1267C>T

ENST00000673839.1:c.139C>T

ENST00000673851.1:c.139C>T

ENST00000673854.1:n.5556C>T

ENST00000673886.1:c.139C>T

ENST00000673890.1:c.139C>T

ENST00000673893.1:c.337C>T

ENST00000673928.1:c.139C>T

ENST00000673936.1:c.139C>T

ENST00000673939.1:c.139C>T

ENST00000673950.1:n.408C>T

ENST00000673978.1:c.277C>T

ENST00000673987.1:c.139C>T

ENST00000674011.1:c.139C>T

ENST00000674018.1:c.139C>T

ENST00000674027.1:n.194C>T

ENST00000674041.1:c.139C>T

ENST00000674052.1:c.358C>T

ENST00000674093.1:c.139C>T

ENST00000674119.1:c.139C>T

ENST00000674135.1:c.316C>T

ENST00000674139.1:c.139C>T

ENST00000674146.1:c.139C>T

ENST00000674149.1:c.139C>T

ENST00000318023.11:c.1990C>T

ENST00000337571.8:c.139C>T

ENST00000349748.7:c.1858C>T

ENST00000356316.7:c.139C>T

ENST00000357568.7:c.2116C>T

ENST00000397163.7:c.2134C>T

ENST00000397200.8:c.598C>T

ENST00000397204.8:c.139C>T

ENST00000466222.6:n.1057C>T

ENST00000561817.5:c.139C>T

ENST00000562199.1:n.138C>T

ENST00000564503.5:c.231C>T

ENST00000565274.5:c.366C>T

ENST00000565559.5:c.316C>T

ENST00000569136.5:c.139C>T

ENST00000569827.5:c.466C>T

NM_000070.2:c.2134C>T

NM_024344.1:c.2116C>T

NM_173087.1:c.1858C>T

NM_173088.1:c.598C>T

NM_173089.1:c.139C>T

NM_173090.1:c.139C>T

NM_024344.2:c.2116C>T

NM_173087.2:c.1858C>T

NM_173088.2:c.598C>T

NM_173089.2:c.139C>T

NM_173090.2:c.139C>T

Likely Pathogenic

PP4 PP3 PP1_Moderate PM2_Supporting PM3_Strong

Evidence Links 0

Expert Panel

Limb Girdle Muscular Dystrophy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CAPN3 Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_000070.3: c.2134C>T variant in CAPN3 is a missense variant predicted to cause the substitution of leucine by phenylalanine at amino acid position 712, p.(Leu712Phe). The variant has been detected in at least six patients with LGMD2A (PMID: 17562833, 26886200, 30919934; GRASP-LGMD Consortium internal data communication), including in a homozygous state without consanguinity in 3 unrelated patients (1.0 pt; PMID: 17562833, 26886200, 30919934). In a fourth patient, the variant was confirmed in trans with a pathogenic CAPN3 variant (c.1981del, p.(Ile661Ter), 1.0 pt) (PMID: 17562833, 26886200, 30919934) (PM3_Strong). At least one patient with this variant displayed a progressive limb girdle pattern of muscle weakness (PP4). This variant was also observed to segregate with autosomal recessive LGMD in three affected family members from one family (PMID: 17562833; PP1_Moderate). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000007757 (4/1180004 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.855, which is above the threshold of 0.70 (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (specifications v2.0.0; 04/29/2026): PM3_Strong, PP4, PP1_Moderate, PM2_Supporting, PP3.

PP4

At least one patient with this variant displayed progressive limb girdle pattern of muscle weakness (PP4).

PP3

The computational predictor Revel gives a score of 0.855, which is above the threshold of 0.70 (PP3). SpliceAI: 0.0100

PP1_Moderate

This variant was observed to segregate with autosomal recessive LGMD in three affected family members from one family (PMID: 17562833; PP1_Moderate).

PM2_Supporting

The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000007757 (4/1180004 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting).

PM3_Strong

The variant has been detected in at least six patients with LGMD2A (PMID: 17562833, 26886200, 30919934; GRASP-LGMD Consortium internal data communication), including in a homozygous state without consanguinity in 3 unrelated patients (1.0 pt; PMID: 17562833, 26886200, 30919934). In a fourth patient, the variant was confirmed in trans with a pathogenic CAPN3 variant (c.1981del, p.(Ile661Ter), 1.0 pt) (PMID: 17562833, 26886200, 30919934) (PM3_Strong).

Curation History

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